Like most autoimmune diseases, Multiple Sclerosis (MS) is more prevalent in women, occurring at an approximate female:male ratio of 3:2. Since the majority of women affected are of child-bearing age, the disease has a significant influence on family planning decisions. Interestingly, numerous studies indicate that the incidence of MS attacks and the overall severity of the disease are reduced during pregnancy. Unfortunately, this period of disease stability is followed by an increase in the number of attacks in the early post-partum period. Since CD4+ T cells play a primary role in the pathogenesis of MS, it is reasonable to hypothesize that changes in their activities either accompany or are responsible for the changes in disease activity that occur during and after pregnancy. More specifically, it is hypothesized that T cell responsiveness during pregnancy is biased for anti-inflammatory, or Th2-like cytokines that protect the patient from clinical disease. By contrast, in the post-partum period, it is hypothesized that T cell responsiveness shifts to favor pro- inflammatory, or Th1-like cytokines that promote MS attacks. The experimental approach to these hypotheses will first involve monitoring of nonspecific and myelin antigen-specific T cell proliferation and cytokine secretion by peripheral blood mononuclear cells collected during each trimester of pregnancy, and the first nine post-partum months. The mechanisms by which these changes occur will then be investigated with two possibilities in mind: 1) that the feto-placental unit contributes to the polarization of the immune response during pregnancy and 2) that the hormonal changes, especially in estrogen secretion, that occur during gestation contribute to changes in T cell function. Most of the experiments in this section of the proposal will involve the use of an animal model of MS, experimental autoimmune encephalomyelitis (EAE). These studies have potential not only to contribute to our knowledge of the mechanisms of disease modulation during pregnancy, but may also provide information concerning the mechanisms that may be responsible for relapse and remission in non-pregnant women and male MS patients.